Passive transdermal device with controlled drug delivery

ABSTRACT

A transdermal device for the controlled administration of a drug to the skin comprises a reservoir (12) for the drug and an electric circuit which includes an electrode system (13, 14) which is operable to actively transport the drug in a controlled manner from the reservoir (12) towards the skin for transport therethrough, the skin not being part of the electric circuit, and the drug passing through an electrode (13) of said electrode system (13, 14) during the active transport to the skin. The electrode (13) is disposed between the reservoir (12) for the drug and an optional transit chamber (15). The electrode (13) can be permeable to the drug or the electrode can function as a gate, being permeable to the drug in the open condition and less permeable to the drug in the closed condition. The operation of the gate can be determined by the composition or the structure of the electrode (13). The device achieves drug delivery rates comparable to those achieved with iontophoretic devices.

TECHNICAL FIELD

This invention relates to a transdermal device for the administration ofdrugs to the skin and, more particularly, to a device for the systemicdelivery of drugs by the transdermal route involving uptake of a givendrug by the skin.

BACKGROUND ART

The administration of drugs percutaneously or transdermally has a numberof advantages and is favoured in the case where drugs are noteffectively administered by the oral route but where systemicadministration is required. This is especially true for drugs which aresubject to a first-pass hepatic metabolism or which are susceptible todeactivation by digestive enzymes.

There are also a number of problems associated with the administrationof drugs by the transdermal route, for example, a rate of uptake of drugwhich is therapeutically effective may not be achievable. The use ofpenetration enhancers, for example, dimethylsulphoxide,N,N-dimethylformamide and others is employed to promote uptake. However,such penetration enhancers are not always effective or sufficient toachieve adequate percutaneous absorption.

Also the manufacture of stable transdermal devices can be a problembecause it may not be possible to find a carrier medium which canmaintain the drug in a stable condition until use and from which thedrug can be successfully transported to and into the skin followingapplication of the transdermal device at the site of administration.

For some drugs such as glyceryl trinitrate fluctuations in blood levelrather than a continuous constant level is required. Thus there is aneed for devices or systems capable of periodic or pulsed drug delivery.

For drugs that are not amenable to passive administration by thepercutaneous route or for drugs that are effectively percutaneouslyabsorbed as charged molecules, iontophoretic drug delivery is gainingincreasing popularity.

However, iontophoretic drug delivery also has a number of problems, notleast of which is the trauma caused by burns and pain which may beassociated with the use of this type of delivery which involvesmigration of drug molecules in the skin under the influence of anelectric field. Hence conventional iontophoresis as a means of drugdelivery may not achieve good patient compliance.

One solution for dealing with the problems associated with iontophoresisis the electrode device of U.S. Pat. No. 4,722,726, one of the statedobjects of which is to provide an iontophoretic drug delivery devicethat inhibits the current carrying capacity of ions in the carriermedium that compete with the active ingredient and lead to progressivediminution of effective drug transfer during the iontophoretic deliverythereof.

U.S. Pat. No. 4,731,049 discloses a cell for electrically controlledtransdermal drug delivery by iontophoresis. The drug is bound on an ionexchange resin or medium or an immobilized ligand affinity mediumlocated in the drug reservoir. Drug delivery occurs upon the applicationof an electrical current of generally small proportions to the reservoiror to an adjacent ion reservoir separated from the drug reservoir by asemi-permeable membrane.

It is an object of the present invention to provide a device and methodfor the delivery of drugs by the percutaneous route which obviates thetrauma in the form of burns and discomfort experienced by the patientand yet achieves an uptake and control of drug by skin which is enhancedwhen compared to conventional passive delivery.

Investigations carried out by us have shown that by using an electriccircuit within a device to actively transport drug from a drug reservoirforming part of said device, but wherein the skin does not form part ofthe circuitry of the device in contradistinction to an iontophoreticdevice, one achieves drug delivery rates greater than those achievedwith conventional passive delivery.

DISCLOSURE OF INVENTION

Accordingly, the invention provides a transdermal device for thecontrolled administration of a drug to the skin, which comprises areservoir for the drug and an electric circuit which includes anelectrode system which is operable to actively transport the drug in acontrolled manner from said reservoir towards the skin for transporttherethrough, the skin not being part of said electric circuit, and thedrug passing through an electrode of said electrode system during saidactive transport to the skin.

In the present Specification the terms drug and active ingredient areused interchangeably.

In one embodiment, the device includes an electrode which is permeableto said drug.

The electrode which is permeable to the drug to be administered canconsist of a porous metallic material. Thus the electrode can consist,for example, of a metal gauze or mesh, of a woven metallic material orof a metal laminate. Suitable metals include platinum, silver or acoated or uncoated metal alloy. Other suitable electrodes include carbonor carbon-based electrodes.

The electrode can also be defined by a closed filament of metal or otherconducting material defining a ring, a square or other suitablegeometric shape.

Alternatively, the electrode which is permeable to the drug beingadministered can consist of porous carbon sheeting or of a range ofpolymeric materials, including conducting polymers, with the requiredconductivity such as those described in the Handbook of ConductingPolymers Vol I and II; T. A. Skotheim, publishers Marcell Dekker Inc.(1986).

The function of said electrode is to spread an appropriate electricalpotential.

In a second embodiment, the device according to the invention includesan electrode which functions as a gate, being permeable to said drug inthe open condition and less permeable to said drug in the closedcondition. The operation of the gate can be determined by thecomposition of the electrode or, alternatively, by the structurethereof.

In the case where the operation of the gate is determined by thecomposition of the electrode, the electrode is suitably composed of apolymeric material with the requisite properties.

When the electrode according to said first or second embodiment is apolymeric material, the polymeric material is suitably one that issusceptible to ion doping or, alternatively, is a polymeric materialhaving ion exchange properties. Polymers which are susceptible to iondoping can be of the donor type or the acceptor type. Following theterminology of semiconductor technology the polymers can be described asn-type or p-type, as appropriate. Suitable examples of polymers with ionexchange properties include both anion exchange resins and cationexchange resins as the circumstances require. Suitable resins aremarketed by Rohm and Haas company under the Trade Mark Amberlite. Othersuitable materials include fluorinated ion exchange polymers such asthat sold under the Trade Mark Nation.

The electrode hereinbefore described can span the width of thereservoir, while having any geometric shape or structure hereindescribed. With such an electrode, the surface thereof distal from thereservoir can be placed in contact with the skin in use. With such anarrangement (hereinafter referred to as Arrangement I) the drug passesthrough the electrode and enters the skin having been activelytransported to the skin surface by the electrode system of the devicewhich includes the electrode hereinbefore described and a furtherelectrode disposed elsewhere in the device, so as to complete theelectric circuit.

In an alternative embodiment, the electrode is disposed between thereservoir for the drug and a transit chamber therefor (hereinafterreferred to as Arrangement II).

The relative sizes of the reservoir and the transit chamber will dependon the particular drug or drugs to be administered. However, in generalthe transit chamber will be of a lesser volume than the reservoir. Thereservoir and transit chamber, if present, together with the electrodedisposed therebetween combined will normally have a thickness of lessthan 5.0 mm, in particular, in the range 0.2-3.0 mm, more especially1.0-3.0 mm.

Using an arrangement of a reservoir and a transit chamber ashereinbefore described, a measured quantity of drug can be activelytransported at selected intervals of time, such as once-a-day, to thetransit chamber from whence it enters the skin over a given period oftime.

The polarity of the electrodes is set according to the charge on the ionwhich is to be transported. The current density is suitably in the range0.2-1.1 mA cm⁻². However, much larger current densities than thoseemployed in conventional iontophoretic devices can be used. The absolutevalue being dependent on the thickness of the transit chamber, if suchis present. In the case of the device according to the invention it iscontemplated that a current density greater than the latter range couldbe used without causing skin trauma because the skin does not form partof the circuitry.

The device according to the invention allows the use of higherelectrical potentials than those employed in conventional iontophoresis.

In an embodiment of the device which allows for periodic or pulsed drugdelivery, the polarity of the electrodes and the magnitude of thevoltage can be systematically altered.

The reservoir can be formed of a shaped mass of a material in which thedrug is distributed or contained for storage.

The transit chamber can either be composed of the same material as thereservoir or of a different material.

Suitably the material of each of the reservoir and the transit chamberis a gel.

Preferred gel materials are formed from gel forming agents selected fromplant extracts, gums, synthetic or natural polysaccharides,polypeptides, alginates and synthetic polymers or a mixture thereof.

Especially preferred gel materials are formed from the gel formingagents agar and carrageenan.

Suitable plant extracts include agar, ispaghula, psyllium, cydonia andceratonia or a mixture thereof.

Examples of suitable gums include guar gum, acacia gum, ghatti gum,karaya gum and tragacanth gum or a mixture thereof.

Suitable synthetic and natural polysaccharides include alkylcelluloses,hydroxyalkylcelluloses, cellulose ethers, cellulose esters,nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran andstarch or starch derivatives and mixtures thereof. An example of apreferred starch derivative is sodium starch glycolate. Especiallypreferred polysaccharides include agar and carrageenan as hereinbeforeindicated.

Suitable polypeptides include zein, gelatin, collagen and polygeline ora mixture thereof.

Suitable alginates include alginic acid, propylene glycol alginate andsodium alginate or a mixture thereof.

An especially preferred synthetic polymer is a carboxyvinyl polymer soldunder the Trade Mark Carbomer.

As used herein the term "agar" is synonymous with "agar-agar".

Other semi-solid type bases include, in particular, media which formliquid crystalline phases such as distilled monoglycerides sold underthe Trade Mark MYVEROL.

However, the reservoir and/or the transit chamber, if present, canequally be formed as a shaped mass of any suitable solid or semi-solidmedium formed with the aid of a solidifying agent. As used herein, theterm solidifying agent embraces hardening, setting, suspending,thickening and like agents.

In the case of the reservoir, the drug or drugs will be uniformlydistributed in the solid, semi-solid or liquid medium.

The surface area of the reservoir and the transit chamber, when present,is preferably in the range 1-10 cm², more especially 2-7 cm².

The reservoir will suitably contain the drug in an amount of 5-100 mg.

The reservoir can include one or more auxiliary agents selected from anantimicrobial agent or a preserving agent, an antioxidant, a pHcontrolling agent, a plasticizer, a surfactant, a penetration enhancer,a humectant, a local anaesthetic or a rubefacient.

Preferred antimicrobial/preserving agents include benzalkonium chloride,cetrimide (cetyltrimethylammonium bromide), benzoic acid, benzylalcohol, Parabens (Trade Mark for the methyl-, ethyl-, propyl- andbutyl-esters of para-hydroxybenzoic acid) chlorhexidine, chlorobutanol,phenylmercuric acetate, borate and nitrate, potassium sorbate, sodiumbenzoate, sorbic acid and thiomersal (mercurithiosalicylate) or amixture thereof.

Preferred antioxidants include sodium metabisulphite, butylatedhydroxyanisole and butylated hydroxytoluene or a mixture thereof.

Preferred pH controlling agents include citric acid and sodium citrate.

Preferred plasticizers include diethylphthalate, dibutylphthalate andtributylcitrate or a mixture thereof.

Preferred surfactants include sodium lauryl sulphate, diethylene glycolmonostearate, propylene glycol monostearate, polyethylene glycols assold under the Trade Mark Macrogol, polysorbates and polyvinyl alcoholor a mixture thereof.

Preferred penetration enhancers include dimethylsulphoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone,N-methyl-2-pyrrolidone, 1-dodecylazacyclo-heptan-2-one, fatty acids suchas oleic acid and salts thereof and terpenes or a mixture thereof.

A preferred humectant is glycerol.

Preferred local anaesthetics include lidocaine, benzocaine, lignocaine,methocaine, butylaminobenzoate and procaine or a mixture thereof. Thedevice would include a local anaesthetic mainly to suppress irritationat the site of application thereof.

In order to form the reservoir and/or the transit chamber, therespective elements are formed separately by adding the gelling agent orthe solidifying agent, as appropriate, to a solvent in an amount thatwill result in a suitably semi-solid or solid mass. The mixture therebyobtained is mixed and optionally heated depending on the agent used soas to produce a uniform medium.

The solvent used is preferably water. However, the solvent used may alsosuitably be an alcohol such as ethanol or stearyl alcohol, glycerol,propylene glycol, polyethylene glycol or a silicone or a mixturethereof, including a mixture with water.

In the case of the reservoir, the drug and any auxiliary agents ashereinbefore described are then added and the resulting mixture mixed touniformity. The shaped mass which forms the reservoir/transit chamber,as appropriate, is formed by moulding, cutting, punching or slicing thesolid or semi-solid mixture so as to form discs or layers of the mixtureas required in a manner known per se.

The drug reservoir for use in the device according to the invention canalso be a liquid contained in a chamber, said chamber having a drugpermeable membrane associated therewith for transport of the drug to theskin in use, optionally through a transit chamber, if present.

With the device according to the invention it is possible to administera drug which is not normally capable of being administered in effectiveamounts passively by the transdermal route and to control, in the senseof increasing or decreasing, the delivery of drugs that do penetrate theskin passively.

Examples of drugs which can be administered using the transdermal deviceaccording to the invention include nicotine, salbutamol andphysostigmine and salts thereof.

Preferred drugs for use in the device according to the invention arebasic compounds and basic salts and zwitterionic compounds, includingpeptides.

When the device according to the invention includes a transit chamber,said transit chamber can include a different drug to that contained inthe reservoir.

According to a further embodiment of the invention, a number ofelectrodes can be disposed in said reservoir.

The transdermal device according to the invention can includecontrolling means operable by a user to selectively transport a drugwithin and from said reservoir. Furthermore, the transdermal deviceaccording to the invention can be programmable.

The device according to the invention can include means for achieving aperiodic or pulsed delivery of drug.

The electric circuit will include a power source which will suitablycomprise conventional miniature or "light-weight" batteries. Forexample, conventional sheet batteries and microbatteries may be used.

The transdermal device according to the invention will comprise ahousing for the various elements thereof.

Preferably, the reservoir, transit chamber, if present, and at least oneelectrode define a unit which is detachably mounted in the housing.

When the transdermal device according to the invention is programmable,a programmable controlling member will be located in the housingtogether with the counter electrode, the power source and othercomponents of the electric circuit. The programmable controlling memberwill comprise the microelectronics and memory necessary to achieve apredetermined mode and timing of drug transport within the device.

The unit may be engageable with the housing in such a manner so as toselect a programme applicable to the active ingredient in the reservoirsuch that the programme, when activated, brings about controlledtransport of active ingredient in said reservoir at selected intervalsof time.

The unit can be replaceable as required, such as every day oronce-a-week or even twice-daily. For example, in order to achieve thecorrect diurnal variation required for certain drugs it may be necessaryto replace the device twice-daily.

The unit can be adapted to engage with and affix to the housing in anysuitable manner, such as by clipping, snap-fit screwing, wedging,bayonet-joint or otherwise securing the respective parts together.

The unit can also be provided with mechanical or electrical contactmeans adapted to select a programme applicable to the active ingredientcontained in the reservoir, which the programmable controlling memberidentifies as containing the or each active ingredient and which saidcontrolling member thus recognises should be transported according to aprescribed regimen.

Thus the housing and unit can have one or more co-operating electricalcontact(s) which on engagement of the respective parts select a givenprogramme.

Preferably, the housing includes means for indicating that the activeingredient is being actively transported and thus delivered at any giventime.

The device may also include means for indicating that the power sourcehas failed or weakened.

The electrical circuit can include alarm means to alert a patient whenit is time for the active ingredient to be delivered, in particular, incircumstances where the device is not worn continuously.

Such alarm means can comprise a timing circuit which will give a signalsuch as a bleep which will prompt the user to apply the device to hisbody.

The housing or the unit preferably includes means for activating theprogramme when the respective parts are in the engaged position. Themeans for activating the programme can be an ON/OFF switch. Such aswitch can be of the type which is activated to the ON position onlywhen the device is in situ on the body of a patient to be treated. TheON/OFF switch may be activated to the ON position by pressure exerted byan attachment means when affixed to the body of a patient.

The electric circuit suitably includes means for monitoring andindicating the content of the active ingredient in the reservoir. Theinclusion of such means would alert a subject undergoing a treatmentregimen using the device if the content of active ingredient is notpresent in an amount effective for a given treatment.

The electric circuit preferably includes overriding means whereby asubject can activate the device to transport and deliver activeingredient at other than a pre-set time up to a predetermined maximumnumber of such activations.

Preferably, the housing and the unit, when in the engaged position, forma single unit, the exterior surface of which, in use, simulates the faceof a time piece and the single unit is attached to or mounted in a strapor bracelet for application of the device to a limb of a body.

More generally, the device according to the invention can be secured tothe body in conventional manner such as by adhesive means, includingbioadhesive means, straps, bracelets, and like securing means.

The housing suitably includes a liquid crystal display (LCD). The LCDmay display current, voltage, timing and other readings as hereinbeforeindicated. The unit may include an ammeter and also a voltage adjusterunder the control of a control circuit. The latter circuit may alsoinclude a galvanostat which keeps the current constant despite varyingresistance of the skin.

The device according to the invention is preferably applied to theflexor surface of the forearm, including the wrist, and also the ankle.In general, such sites show the greatest consistency from individual toindividual in terms of drug absorption relative to other sites for drugadministration because of the amount of tissue at such sites. Bloodvessels are found close to the surface of the skin at such sites whichfacilitates the up-take of drugs into the systemic circulation.

The reservoir and/or the transit chamber, if present, can be housed in areceptacle which is drug impermeable, thereby, ensuring a unidirectionaltransport of drug towards to the skin.

The invention will be further illustrated by the following descriptionof an embodiment thereof given by way of example only with reference tothe accompanying Drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a transdermal device accordingto the invention (Arrangement II);

FIG. 2 is a circuit diagram of the circuit employed in the devicedepicted in FIG. 1;

FIG. 3 is a graphic representation of nicotine release profile (mg)versus time (h.) for a device according to the invention relative tocontrols as hereinafter described;

FIG. 4 is a graphic representation of the effect of the current densitythrough a device according to the invention on the quantity of nicotinereleased (mg) as a function of time (h) as hereinafter described;

FIG. 5 is a graphic representation of the quantity of drug released (mg)versus time (h.) for 20 mg nicotine-containing discs across humanstratum corneum in a device according to the invention relative to acontrol;

FIG. 6 is a graphic representation of the delivery of physostigminehemisulphate (mg) across Sha-Sha mouse skin in an Arrangement I-typedevice according to the invention using different currents versus time(h) relative to passive delivery;

FIG. 7 is a graphic representation of the delivery of physostigminesalicylate (mg) across Sha-Sha mouse skin in an Arrangement I-typedevice according to the invention using different currents versus time(h) relative to passive delivery;

FIG. 8 is a graphic representation of the delivery of physostigminesalicylate (mg) across Sha-Sha mouse skin in an Arrangement I-typedevice according to the invention using different currents versus time(h) relative to passive delivery, using a different drug loading andsurface area relative to that used in relation to FIG. 7; and

FIG. 9 is a graphic representation of the delivery of physostigminesalicylate (mg) across whole thickness human cadaver skin in anArrangement I-type device according to the invention using differentcurrents versus time (h) relative to passive delivery.

BEST MODE FOR CARRYING OUT THE INVENTION

Referring to FIG. 1 there is illustrated a transdermal device indicatedgenerally at 10 comprising a housing 11 for a reservoir 12 for a druguniformly distributed in agar gel and an electric circuit which includesan electrode 13 of platinum mesh gauze (Johnson Matthey 52 mesh Lot No.625590) which is permeable to said drug and a further electrode 14, theelectrode 13 separating the reservoir 12 from a transit chamber 15 alsocomposed of agar gel. The device 10 depicted in FIG. 1 is a device ofthe type herein referred to as an Arrangement II.

The housing 11 also includes a programmable controlling unit 16 withappropriate circuitry and a power supply 17.

The electrode 13 is connected by a lead 18 through a touch button 19 tothe circuitry in the housing 11. The electrode 14 consists of a foil ofplatinum which is connected to the circuitry in the housing 11 by a lead20 having an associated touch button 21 and which when the device isactivated to transport drug within the reservoir 12 allows the circuitto be completed.

The reservoir 12, the electrode 13 and the transit chamber 15 define aunit which is releaseably attachable to the housing 11 by means of aconnector 22 disposed on a surface 23 of an insulating material such asa suitable plastics material. The connector 22 is engageable in arecognition position 24 in the housing 11. The connector 22 onengagement of the aforementioned unit with the housing 11 selects agiven programme applicable to the drug contained in the reservoir 12 andsaid programme when activated brings about the desired transport of thedrug to the transit chamber 15 and hence by passive diffusion thereafterto the skin.

The programmable controlling unit 16 includes an ammeter 25, agalvanostat 26 and an LCD 27 with appropriate switching arrangementswhich can display current, voltage and time and a time keeping componentwith provision for an audible alarm which alerts a subject when it istime for the drug to be delivered, if the device is not worncontinuously. The unit 16 also includes an ON/OFF button 28 foractivating the program when the unit comprising the reservoir 12, andthe housing 11 are in the engaged position and an override button 29whereby a patient can activate the device to transport the drug at otherthan a pre-set time up to a predetermined maximum number of suchactivations as hereinbefore described.

An LED (light emitting diode) 30 is also provided in the unit 16 toindicate satisfactory operation of the device, for example so as toindicate that the drug is being actively transported. The LED 30 alsoindicates if the power supply 17 has failed or weakened and will give anindication of the content of the drug in the assembled device.

The device 10 is attached to the site of application by means of a strap31 having at the free ends thereof the cooperating elements of aconventional clasp 32.

The main components of the circuit employed in the device 10 aredepicted in the circuit diagram corresponding to FIG. 2. Said componentsare as follows:

PC--a programmable controlling circuit, including an audible alarmmeans;

PS--a power supply;

A--an ammeter;

G--a galvanostat;

SS--a selector switch;

O--an override switch;

LCD--a liquid crystal display for current, voltage, time, etc. asselected; and

LED--a visible signal of delivery of drug, failure or weakening of powersupply, or content of drug in the device 10.

RP--a recognition position.

Most of the foregoing features can be incorporated into an appropriatemicrochip.

In Vitro Studies--Arrangement II.

A series of in vitro experiments were carded out to assess thetransdermal device according to the invention of the type hereinreferred to as an Arrangement II. In these experiments an artificialmembrane of Visking (Visking is a Trade Mark) and human stratum corneumwere used as the barriers to diffusion into glass, custom builtdiffusion cells based on a commercially available Franz cell (Franz, T.J., (1975); J. Invest. Dermatol. 64, 190). An assembly consisting of areservoir, transit chamber, electrodes, galvanostat and ammeter of thetype used in the transdermal device depicted in FIG. 1 and a voltmeterwas placed on top of the cell and secured in place by means of a Teflon(Teflon is a Trade Mark) holder.

For the experiments with Visking the solution used in the receptorcompartment of the cell was distilled water, whereas for the experimentsusing human stratum corneum a phosphate buffer at pH 7.4 was used in thereceptor compartment. The phosphate buffer solution of pH 7.4 used inthe latter experiments was prepared using disodium hydrogenorthophosphate (BDH) 14.7 g/l and sodium dihydrogen phosphate(Riedel-deHaen) 2.66 g/l in distilled water. The receptor solution wasstirred throughout the experiment by a star-headed magnet to providecontrol of the cell hydrodynamics.

The cell was immersed in a water bath, the temperature of which was keptconstant at 37° C. to mimic body temperature. Samples of receptorsolution were withdrawn through the side arm or sample port of the cellat regular intervals during the course of the experiments and replacedby fresh receptor solution in conventional manner.

The Visking membrane was prepared from 4 cm length sections of Viskingtubing 18/32 which were boiled in distilled water before use to free themembrane of any impurities.

Human stratum corneum membrane was prepared in accordance with themethod of Kligman, A. M. and Christophers, E. ((1963) ArchivesDermatology 88, 702-705). The stratum corneum and the epidermis wereseparated from the other skin layers from a section of full thicknessabdominal skin and the excess subcutaneous fat removed. The remainder ofthe tissue was immersed in distilled water at 60° C. for 2 min. Theusual trypsinisation step to remove the epidermis was omitted. This wasconsidered to be unnecessary as it is known that the stratum corneum isthe rate limiting barrier to diffusion of drugs through the skin. Thestratum corneum was then stretched onto a wire mesh dermal side down anddried overnight in a desiccator at 25% relative humidity. When dry, itwas sealed in a plastics sachet and stored in a fridge until needed.

Preparation of Discs.

Discs of gel No. (1) (Oxoid Ltd. Lot No. 238 14790) were prepared byadding 4% of the solid to distilled water (20 ml) and the resultantmixture was heated slowly. When hot, the viscous solution was pouredinto a standard size petri dish and allowed to set. Circular discs 1.84cm. in diameter were cut out and used as the transit chamber in theassembly. A range of discs ranging in thickness from 0.10-0.45 cm werestudied.

The drug loaded discs to serve as the reservoir in the assembly werealso made of No. (1) gel in which the drug was dissolved. The drugloaded discs were prepared in the same manner as for the discs to serveas the transit chamber with the addition of the requisite amount of drugprior to the heating step. The drugs used in the evaluation of thedevice were nicotine (vacuum distilled, The Nicobrand Company,Coleraine, County Derry, Northern Ireland.) and salbutamol sulphate B.P. Circular discs, with a cross-sectional area of 2.67 cm² and a volumeof 1.81 cm³ were cut as required. For both salbutamol and nicotine thedrug dissolved in water with a little stirring.

Analytical Methods

Salbutamol was detected in the samples withdrawn from the diffusion cellby high performance liquid chromatography (HPLC).

HPLC samples were injected onto a μ Bondapak C₁₈ Radical-Pak (Bondapakand Radical-Pak are Trade Marks) reversed column using a Waters 712 WISP(WISP is a Trade Mark) auto-injector. The method of detection employedwas UV spectroscopy using a Waters model 455-LCUV spectrophotometer. Themobile phase consisted of acetonitrile (Lab Scan) (92:8) containing 12g/l NaH₂ PO₄. The flow rate was set at 2 ml/min. The detectionwavelength was set at 276 nm. The injection volume of the sample underanalysis was 20 μl. An external standard method was used by means of aWaters 740 Data Module integrator to calculate the concentration ofsalbutamol. Using this method a sharp peak was observed at a retentiontime of 6 min. The system was programmed to recalibrate the standardafter every 5 samples in order to optimise the accuracy of the analysis.

Determination of nicotine was achieved by UV spectroscopy using a PYEUnicam SP8200 UV/VIS Spectrophotometer with the detection wavelength setat 260 nm.

Control assemblies comprised: a) an assembly consisting of a reservoir(single gel system); b) an assembly consisting of a reservoirsuperimposed on a transit chamber (double gel system); and c) anassembly as for b) but with a platinum mesh disposed between thereservoir and the transit chamber.

Permeation Studies Across Membranes.

Release of both salbutamol and nicotine from control b) showed a releaseprofile characteristic of a passive system. The lag-time for thedelivery through control b) was greater than the value obtained fromcontrol a), indicating retarded transport when a transit chamber ispresent.

The extent to which the transit chamber acts by retarding the deliveryof drug can be explained in terms of gel thickness in that chamber.Decreasing the thickness of the gel results in an increased rate of drugpenetration through the Visking membrane. Thus, reducing the thicknessof the transit chamber enhances the initial rate of drug transport.

As might be expected greater quantities of drug were released from gelsthat contained higher initial concentrations. Increasing theconcentration of drug in the reservoir was also seen to reduce thelag-time.

Incorporation of the platinum gauze (control c)) between the two gelsconstituting the double gel system introduces a new barrier to drugdiffusion. The degree to which the platinum acted as a barrier to drugdiffusion depended on the pore size of the mesh itself. The greater thevoid surface area on the gauze the faster the rate of drug penetration.Introduction of a silver gauze barrier between the two gels also servedas a barrier to drug permeation and since the degree of void area fordrug penetration was less than that in the platinum gauze membrane, therate of drug release was hindered to a greater extent.

Device According to the Invention.

Application of a potential difference across the reservoir between thegauze and the electrode applied to the side furthest away from themembrane barrier results in an increase in the rate of penetration ofdrug through the double gel system. The ensuing electric current resultsin the movement of charged ions in the drug loaded gel. The basis forthis electrolytic movement is provided by Faraday's laws ofelectrolysis. In the device according to the invention the drug ions arecarried through the reservoir from the solid platinum electrode to theplatinum gauze electrode. This results in a build up of drugconcentration at the interface between the gels. However, due to theporous nature of the gauze membrane, ions gathering at the surface ofthe electrode may permeate into the second gel (transit chamber) whichis initially unloaded, resulting in enhanced movement of drug throughthe gauze barrier and into the unloaded gel. This provides a meanswhereby the concentration of drug in the unloaded gel can be controlledand maintained. The actual diffusion of the drug across the Viskingbarrier is controlled and depends on the concentration that has beenbuilt up in the originally unloaded gel in the transit chamber.

The overall rate of delivery (R_(total)) of drug from the assembly canbe described by the combination of electrically assisted (R_(elec)) andpassive transport (R_(p)) as

    R.sub.total =R.sub.p +R.sub.elec

It should be emphasised here that the transport through the membrane inthe next phase of delivery takes place by diffusion and is not assistedby current as in the case of conventional iontophoretic systems wherethe membrane (i.e. skin) forms part of the electric circuit.

By comparison with both control b) and control c), the enhancement indrug penetration is clearly evident. Release rates for the three systemsare shown to be of the order, platinum barrier system <double gelsystem<device according to the invention as shown in FIG. 3 which is acomparison of release profiles in the receptor compartment of thediffusion cell obtained from control b) (-- --), control c) (--□--) andthe device according to the invention (-- --) using a current of 0.5 mA.

The effect of applying a range of currents 0.5-3.0 mA to the deviceaccording to the invention, is shown in FIG. 4. As the current isincreased the rate of drug transport into the receptor compartment ofthe diffusion cell also increases and as is the case for single geliontophoretic systems the release profiles tend to become linear withtime. In FIG. 4, curve --□-- represents 0.5 mA, curve -- -- represents1.0 mA, curve -- -- represents 2.0 mA and curve -- -- represents 3.0 mA.

Permeation Studies Across Excised Human Stratum Corneum.

Preliminary investigations across excised human stratum corneum haveillustrated similar trends in drug penetration from the device accordingto the invention to those observed using Visking ie., the same order ofdrug permeation is observed for each of the three double gel systemsnamely controls b) and c) and the device according to the invention. Thedegree of permeability using a 20 mg nicotine patch (11.04 mg/ml),unloaded gel thickness of 2.2 mm for the double gel system, gives quitea slow release of nicotine (FIG. 5). Application of an electricalpotential resulting in a current of 0.5 mA flowing through the reservoirgives an approximate 2 fold enhancement in drug penetration. In FIG. 5,curve --□-- represents control b) and curve -- -- represents the deviceaccording to the invention. The effect of passing greater currentsthrough the drug loaded gels needs to be investigated as studies to datehave been confined to the use of a 0.5 mA current.

In Vitro Studies--Arrangement I.

A further series of in vitro experiments were carried out using asbiological membranes Sha-Sha mouse skin and whole thickness human skinin conjunction with a device according to the invention without atransit chamber and herein referred to as Arrangement I. The conditionswere generally as set out for the in vitro studies carried out onArrangement II, except as hereinafter described. Thus, in theseexperiments a carbon-based porous electrode (3M Company) was used. Thedrug employed was physostigmine either as the hemisulphate orsalicylate.

Experiment a).

Drug: physostigmine hemisulphate.

Drug loading: 15.3 mg (=7.84 mg/ml).

Vehicle: 4% agar/water.

Surface area: 2.37 cm².

Receptor solution: isotonic phosphate buffer, pH 7.4.

Membrane: Sha-Sha mouse skin.

The results are depicted in FIG. 6.

In FIG. 6 curve represents conventional passive delivery (0.00 mA) whilethe remaining curves represent delivery from Arrangement I. Curverepresents a current of 0.5 mA, curve represents a current of 1.0 mA andrepresents a current of 2.0 mA. A greater than tenfold enhancement intransport is evident with Arrangement I.

Experiment b).

Drug: physostigmine salicylate.

Drug loading: 19.5 mg (=10 mg/ml).

Vehicle: 4% agar/water.

Surface area: 2.37 cm².

Receptor solution: isotonic phosphate buffer, pH 7.4.

Membrane: Sha-Sha mouse skin.

The results are depicted in FIG. 7.

In FIG. 7 curve represents conventional passive delivery (0.00 mA) whilethe remaining curves represent delivery from Arrangement I. Curverepresents a current of 0.5 mA, curve represents a current of 1.0 mA andrepresents a current of 2.0 mA. It will be observed from FIG. 7 that aneven greater enhancement in transport is evident when the salt form ofthe drug is changed to the salicylate.

Experiment c).

Drug: physostigmine salicylate.

Drug loading: 30 mg (=10 mg/ml).

Vehicle: 4% agar/water.

Surface area: 7.00 cm².

Receptor solution: isotonic phosphate buffer, pH 7.4.

Membrane: Sha-Sha mouse skin.

The results are depicted in FIG. 8.

In FIG. 8 curve represents a current of 1.475 mA, curve represents acurrent of 2.950 mA and represents a current of 4.525 mA. A furtherrelative enhancement in transport is evident under the conditions usedin Experiment c) relative to Experiment b).

Experiment d).

Drug: physostigmine salicylate.

Drug loading: 19.5 mg (=10 mg/ml).

Vehicle: 4% agar/water.

Surface area: 2.37 cm².

Receptor solution: isotonic phosphate buffer, pH 7.4.

Membrane: Whole thickness human cadaver skin.

The results are depicted in FIG. 9.

FIG. 9 shows enhanced delivery of physostigmine from Arrangement I whencompared with conventional passive transport (curve (0.00 mA)). In FIG.9 curve represents a current of 0.5 mA, curve represents a current of1.0 mA and represents a current of 2.0 mA.

The experiment shows that Arrangement I was also effective when theSha-Sha mouse skin was replaced by whole thickness human skin.

This invention is not limited to the embodiments described above whichmay be modified and/or varied without departing from the scope of theinvention.

We claim:
 1. A transdermal device for the controlled administration of a drug to the skin, which comprises a reservoir for the drug, an electric circuit comprising an electrode system of at least two electrodes in which at least one of the electrodes is permeable to the drug, which electrode system has means for electrolytically transporting the drug in a controlled manner within the device by a potential difference applied to the electrodes, the drug passing through the at least one drug permeable electrode of the electrode system, wherein the electrodes are disposed internally of the device such that the skin does not form a part of the electric circuit, means for securing the device in contact with the external skin of a patient, the drug being actively transported from the reservoir in the direction of the skin for transport therethrough, by energising the electrodes.
 2. A transdermal device according to claim 1, wherein the drug is one which is not normally capable of being administered passively by the transdermal route.
 3. A transdermal device according to claim 1, wherein the at least one drug permeable electrode comprises a porous metallic material.
 4. A transdermal device according to claim 3, wherein the at least one drug permeable electrode comprises a metal gauze.
 5. A transdermal device according to claim 3, wherein the at least one drug permeable electrode comprises a woven metallic material.
 6. A transdermal device according to claim 3, wherein the at least one drug permeable electrode comprises a metal laminate.
 7. A transdermal device according to claim 3, wherein the metal is selected from the group consisting of platinum, silver, a coated metal alloy and an uncoated metal alloy.
 8. A transdermal device according to claim 1, wherein the at least one drug permeable electrode comprises carbon sheeting.
 9. A transdermal device according to claim 1, wherein the at least one drug permeable electrode functions as a gate, being permeable to the drug in the open condition and less permeable to the drug in the closed condition.
 10. A transdermal device according to claim 9, wherein the operation of the gate is provided by the at least one drug permeable electrode being constructed of an ion exchange material.
 11. A transdermal device according to claim 9, wherein the operation of the gate is provided by the at least one drug permeable electrode formed of a material of variable pore sizes.
 12. A transdermal device according to claim 1, wherein the at least one drug permeable electrode electrode which comprises a polymeric material.
 13. A transdermal device according to claim 12, wherein the polymeric material is susceptible to ion doping.
 14. A transdermal device according to claim 12, wherein the polymeric material has ion exchange properties.
 15. A transdermal device according to claim 1, wherein the at least one drug permeable electrode electrode spans the width of the reservoir.
 16. A transdermal device according to claim 1, wherein the at least one drug permeable electrode electrode spans the width of the reservoir and wherein the surface of said at least one drug permeable the electrode distal from the reservoir is placed in contact with the skin in use.
 17. A transdermal device according to claim 1, further comprising a transit chamber adapted for contact with the skin, wherein the said at least one drug permeable electrode is disposed between the reservoir for the drug and the transit chamber therefor.
 18. A transdermal device for the controlled administration of a drug to the skin, which comprises a reservoir formed of a shaped mass of a material in which the drug is distributed for storage, a transit chamber adapted for contact with the skin, and an electric circuit comprising an electrode system of at least two electrodes, which electrode system is operable to actively transport the drug electrolytically in a controlled manner within the device, the drug passing through an electrode of the electrode system, which electrode is permeable to the drug and is disposed between the reservoir for the drug and the transit chamber therefor, the electrodes being disposed internally of the device such that the skin does not form part of the electric circuit and such that the drug is electrolytically transported from the reservoir in the direction of the skin for transport therethrough, by energising the electrodes.
 19. A transdermal device according to claim 18, wherein the transit chamber is composed of the same material as the reservoir (12).
 20. A transdermal device according to claim 18, wherein the transit chamber is composed of a material which is different to that comprising the reservoir.
 21. A transdermal device according to claim 18, wherein the material of each of the reservoir and the transit chamber is a gel.
 22. A transdermal device according to claim 21, wherein the gel material is formed from a gel forming agent selected from the group consisting of plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers and mixtures thereof.
 23. A transdermal device according to claim 21, wherein the gel forming agent selected from the group consisting of agar and carrageenan.
 24. A transdermal device according to claim 18, wherein the transit chamber includes a different drug to that contained in the reservoir.
 25. A transdermal device according to claim 18, wherein the drug is one which is not normally capable of being administered passively by the transdermal route.
 26. A transdermal device according to claim 18, wherein the drug is salbutamol.
 27. A transdermal device according to claim 18, wherein the drug is nicotine.
 28. A transdermal device according to claim 18, wherein a plurality of electrodes permeable to the drug are disposed in the reservoir.
 29. A transdermal device according to claim 18, wherein the device includes controlling means operable by a user to selectively transport the drug within and from the reservoir.
 30. A transdermal device according to claim 18, further comprising programmable means for controlling the selective transport of the drug within and from the reservoir.
 31. A transdermal device according to claim 18, further comprising means for achieving a periodic or pulsed delivery of drug.
 32. A transdermal device according to claim 18, further comprising housing means, wherein the reservoir, transit chamber and at least one electrode define a unit which is detachably mounted in the housing means.
 33. A transdermal device according to claim 1, wherein the drug is salbutamol.
 34. A transdermal device according to claim 1, wherein the drug is nicotine.
 35. A transdermal device according to claim 2, wherein a plurality of electrodes permeable to the drug are disposed in the reservoir.
 36. A transdermal device according to claim 1, wherein the device includes controlling means operable by a user to selectively transport the drug within and from the reservoir.
 37. A transdermal device according to claim 1, further comprising programmable means for controlling the selective transport of the drug within and from the reservoir.
 38. A transdermal device according to claim 1, further composing means for achieving a periodic or pulsed delivery of drug.
 39. A transdermal device according to claim 1, further comprising housing means, wherein the reservoir and at least one electrode define a unit which is detachably mounted in the housing means.
 40. A method for the controlled passive transdermal delivery of at least one drug to a subject, comprising the steps of:(a) attaching a transdermal device to the skin of the subject, wherein the transdermal device comprises:i) the at least one drug; ii) a reservoir for storing the at least one drug; and iii) an electric circuit comprising an electrode system of at least two electrodes, wherein the electrodes are disposed internally in the device such that the skin does not form part of the electric circuit and wherein the drug is actively transported from the reservoir in the direction of the skin when the electric circuit is energised; (b) providing a voltage potential across the electric circuit electrodes causing electrolytic transport of the at least one drug in a controlled manner within the device between the electrodes to provide controlled delivery of the at least one drug to the skin of the subject; and (c) delivering the at least one drug to the subject via controlled passive transdermal delivery.
 41. A method for the controlled passive transdermal delivery of at least one drug to a subject, comprising the steps of:(a) attaching a transdermal device to the skin of the subject, wherein the transdermal device comprises:i) the at least one drug; ii) a reservoir for storing the at least one drug; iii) an electric circuit comprising an electrode system of at least two electrodes in which at least one of the electrodes is permeable to the at least one drug, wherein the electrodes are disposed internally in the device such that the skin does not form part of the electric circuit and wherein the drug is actively transported from the reservoir in the direction of the skin and through the at least one electrode permeable to the at least one drug when the electric circuit is energised; iv) a transit chamber adapted for contact with the skin, wherein the electrode permeable to the at least one drug is disposed between the reservoir for the drug and the transit chamber; (b) providing a voltage potential across the electric circuit electrodes causing the electrolytic transport of the at least one drug in a controlled manner within the device between the electrodes and from the reservoir through the electrode permeable to the at least one drug to the transit chamber to allow for the controlled delivery of the at least one drug to the skin of the subject from the transit chamber; and (c) delivering the at least one drug to the subject via controlled passive transdermal delivery. 